Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Fan, C.; Cohen, A. A.; Park, M.; Hung, A. F.-H.; Keeffe, J. R.; Gnanapragasam, P. N.; Lee, Y. E.; Kakutani, L. M.; Wu, Z.; Malecek, K. E.; Williams, J. C.; Bjorkman, P. J.

doi:10.1101/2022.06.28.497989

bioRxiv · 10.1101/2022.06.28.497989

Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Fan, C.·Cohen, A. A.·Park, M.·Hung, A. F.-H.·Keeffe, J. R.·Gnanapragasam, P. N.·Lee, Y. E.·Kakutani, L. M.·Wu, Z.·Malecek, K. E.·Williams, J. C.·Bjorkman, P. J.

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Abstract

Protection from SARS-related coronaviruses with spillover potential and SARS-CoV-2 variants could prevent and/or end pandemics. We show that mice immunized with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicit cross-reactive anti-sarbecovirus antibodies against conserved class 1/4 and class 3 RBD epitopes. Monoclonal antibodies (mAbs) identified from initial screening of <10,000 single B-cells secreting IgGs binding two or more sarbecovirus RBDs showed cross-reactive binding and neutralization of SARS-CoV-2 variants and animal sarbecoviruses. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes and revealed neutralization mechanisms, potentials for intra-spike trimer crosslinking by single IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticles to identify therapeutic pan-sarbecovirus and pan-variant mAbs and to elicit them by vaccination.

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Fan, C., Cohen, A. A., Park, M., Hung, A. F.-H., Keeffe, J. R., Gnanapragasam, P. N., Lee, Y. E., Kakutani, L. M., Wu, Z., Malecek, K. E., Williams, J. C., Bjorkman, P. J.. 2022-06-28. Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes. https://doi.org/10.1101/2022.06.28.497989

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